SUMMARY Traumatic brain injury (TBI) is a leading contributor to death and disability in the USA, yet widely effective treatments remain elusive and, except for a lengthy program of rehabilitation, no effective treatment for TBI is available. Therefore, there is a critical need in new therapeutic approaches which can maximally preserve brain tissue and facilitate functional recovery after TBI. In the last two decades substantial efforts have been invested in developing medicines for TBI, but these efforts have not resulted in clinically-efficacious therapies. These failures highlight the need for development of new therapeutic ideas and approaches for reducing neuronal injury secondary to TBI. Among possible strategies, effective treatments with broad therapeutic windows are likely to be the most valuable because of the unexpected events leading to brain trauma. Our data presented indicate that activation of ?7 nicotinic acetylcholine receptors (nAChRs) can significantly reduce brain injury following TBI. A novel therapeutic paradigm has been introduced that converts endogenous choline/ACh into potent therapeutic agents after brain trauma by inhibiting ?7 nAChR desensitization using Type-II positive allosteric modulators (i.e. PAMIIs), such as PNU120596. Our data demonstrate that PNU120596 administered intravenously after controlled cortical impact (CCI) significantly reduces brain injury and astrogliosis in rats and suggest that novel PAM II agents represent a therapeutic opportunity in TBI. Our efforts to discover novel entities has produced EPGN1137, a compound with suitable potency in the reactivation of ?7 nAChRs, drug-like characteristics, and which demonstrates preliminary efficacy in a related model of ischemic stroke. A plan to test Epigen candidate PAM IIs in CCI models of TBI includes: A) Re- synthesis of novel candidate molecules with appropriate ?7 nAChR reactivation efficacy, B) a detailed pharmacokinetic assessment of the PAM II candidates to design dosing schedules for efficacy studies; and C) an evaluation of efficacy in the CCI model of TBI. We expect to identify at least one PAM II with suitable efficacy that may be progressed into pre-clinical development or define criteria for the selection of lead PAM II candidates.